The prefrontal cortex (RFC) subserves many higher cognitive functions, including working memory, and is often impaired as a result of Parkinson's and Alzheimer's Diseases, aging, and traumatic brain injury (TBI). Working memory is the temporary maintenance of information "online" required for the planning and guiding of behavior, and lies at the core of many higher cognitive functions. Although dopamine signaling in PFC dysfunction has received much attention, the contribution of norepinephrine (NE) is disproportionately under studied. Our recent data indicate that TBI in rodents can cause profound working memory impairments in the absence of overt neuronal loss in the medial PFC (mPFC), which includes the prelimbic/infralimbic (PL/IL) cortices. This working memory deficit is associated with increased activity of the rate-limiting enzyme in NE synthesis, tyrosine hydroxlase, elevated levels of the GABA synthesizing enzyme GAD67, and may involve altered protein kinase A, protein kinase C and/or calcium/calmodulin-dependent protein kinase II activities in the PL/IL. Based on these and other observations, the present proposal will test the overall hypothesis that high levels of NE in the PL/IL cortices is causally related to TBI-associated working memory deficits. Consequently, post-injury modulation of adrenergic receptor-mediated signaling will alleviate these deficits. The proposal has three specific aims to test the veracity of the hypothesis. Aim 1: To examine if the biosynthesis of NE in the PL/IL cortices is increased following TBI and to assess its role in working memory deficits. Aim 2: To determine if TBI alters adrenergic receptor levels in the PL/IL and to assess the contribution of adrenergic receptors to working memory deficits and GABA synthesis. Aim 3: To determine if NE-activated intracellular protein kinase activity in the PL/IL cortices following TBI contributes to working memory deficits. These studies will provide insight into the neurochemical basis of prefrontal dysfunction following brain injury. As deficits in prefrontal function, especially working memory impairments, lie at the core of many higher cognitive dysfunctions, the results from these studies could guide treatment strategies to alleviate PFC damage following injury and other neurological disorders.